The purposes of this work are to elucidate the molecular and physical chemical bases of the gelation of sickle cell hemoglobin and to employ such knowledge to inhibit gelation and its pathogenic consequences. The pathogenesis of sickle cell disease depends on the formation of an intraerythrocytic gel consisting of fibers of polymerized deoxygenated sickle cell hemoglobin. Inhibition of gelation might be obtained through modification of the hemoglobin or through diversion of the pathogenic process to states which are minimally or less pathogenic. In this project we are studying the equilibria, kinetics and rheological properties of the gel. Since small changes in free energy probably induce changes in the most stable state, modification of equilibria may be critical in pathogenesis. Our work is directed toward the now separable stages of polymerization and phase separation. Since rheological properties lie at the basis of red cell rigidity and thus pathogenesis, these properties are most critical in potential clinical control of the disease. The methods we are employing include analytical ultracentrifugation, light scattering and viscosity studies.